Presbyopia, or age-related loss of accommodative ability, is a very common ocular pathology. Accommodative ability refers to the capacity of the eye to focus for near vision by changing the shape of the lens to become more convex. The ocular tissues involved in the accommodative response include the lens, the zonules (suspensory ligaments) of the lens, and the ciliary muscle. These structures function together in accommodating the eye for focusing on close objects.
Within the eye, the lens is centrally suspended between the anterior and posterior chambers, behind the pupillary opening of the iris. The lens is supported by a radially oriented array of zonules which extend from the lateral edges of the lens to the inner border of the circumferential ciliary muscle. The ciliary muscle is attached to the scleral coat of the eye.
At rest, the eye is focused for distant vision with the lens held in a somewhat flattened, or slightly convex, shape by tension exerted on its periphery by the zonules. These ligaments pull the edges of the lens towards the ciliary body. During accommodation, the shape of the lens becomes more convex. This action is achieved through contraction of the ciliary muscle which allows the ciliary attachment of the zonules to move inward towards the lens, thereby reducing the tension in the zonules. This reduction in tension allows the lens to increase in convexity, resulting in an increase in dioptric power which enables near objects to be imaged clearly on the retina.
Loss of accommodative ability can be measured as the progressive regression of the near point of accommodation, which is the closest point for which the eye can accommodate so that a clear image is formed on the retina. The near point of accommodation is nearest to the eye in the young and recedes gradually until about the age of 45 years, when a much more rapid recession of the near point ensues. This recession continues unabated until about the age of 60 years, by which time all accommodation has been lost.
The amplitude of accommodation may also be quantified by measuring the dioptric power of the eye, a measure of refractive power. The dioptric power is measured in diopters (D). Accomodative ability is greatest in childhood and slowly decreases until it is lost in middle age. At the age of 8 years the dioptric power of the eye can be raised by accommodation to approximately 14 D; at the age of 20 years this has fallen to 11D. At the age of 30 years the eye can accommodate 9 D. By the age of 50 years, less than 2 D remain.
By the age at which the loss of the amplitude of accommodation has made the near point so far removed that the subject cannot read fine print, the eye has become presbyopic. Presbyopia is the age-related recession of the near point of accommodation, and usually is evident by the age of 45 years. In an otherwise normal eye, convex glasses are prescribed to correct for the decrease in the accommodative power of the lens. In a myope, bifocals will be needed. The necessity for corrective lenses in essentially all people as they age imposes obvious financial costs. Safety and efficiency are also threatened when corrective lenses are not used for reasons of convenience, accessibility or cosmetic undesirability.
The etiology of presbyopia is not yet well defined, but changes in several tissues, including lens, zonules, and ciliary muscle, probably contribute to the progressive loss of accomodative ability. With age, the lens mass hardens, adhesion between the lens fibers increases, and the elasticity of the lens capsule decreases; the lens finally is unable to assume a more convex, accomodated shape despite maximal contraction of the ciliary muscle. The progressive rigidity of the lens is exacerbated by an apparent loss of refractivity of the lens tissue. The loss of refractive power in the lens tissue means that the age-impaired lens needs to assume a more convex shape for close focusing than does the lens of a younger person.
The progressive lens hardening and loss of refractive power appear to be inevitable with age. The prevailing view is currently that treatment of presbyopia is not feasible, except for the symptomatic prescribing of corrective glasses.
Age related changes in the zonules may also contribute to the development of presbyopia. With age, the location of zonule attachment to the lens capsule shifts from the lens equator onto the anterior surface of the crystalline lens. This apparently necessitates a greater movement of the ciliary muscle to produce a unit change of accommodation with age.
Although early studies suggested that changes in the ciliary muscle with age might contribute to the loss of accommodation, recent studies indicate that the ciliary muscle does not change substantially with age, but rather is relatively immobilized by its attachments to the lens, choroid and scleral spur.
The ciliary muscle controls the shape of the lens and thereby implements accommodation. Like most smooth muscles, the ciliary muscle has a dual innerration, receiving both sympathetic and parasympathetic fibers. In the ciliary muscle, the contraction necessary for accommodation is under parasympathetic (cholinergic) control, which clearly predominates. Opposing cholinergic control, the sympathetic (adrenergic) innerration, which plays a minor role, is responsible for relaxation of the ciliary muscle or inhibition of accommodation.
The role of sympathetic innervation in accommodation in humans has been the subject of several recent pharmacological investigations. The ciliary muscle can be made to "dilate" (the ciliary muscle ring widens) by alpha-adrenergic stimulation, which causes decreased accommodation. In one study, an alpha-adrenergic antagonist caused an average increase in accommodative amplitude of 1.5 D, which peaked 40 minutes after instillation and decayed rapidly to baseline in less than 2 hours. The effect appeared specifically related to alpha-adrenergic receptors in the ciliary muscle, rather than a non-specific effect on either pupil size or vasodilation of blood vessels.
The ciliary muscle also has beta-adrenergic receptors which, when stimulated, trigger ciliary muscle relaxation. Conversely, beta-adrenergic antagonists, like timolol, in certain circumstances can cause a net increase in accommodation, which is enhanced by concurrent parasympathetic activity. This effect has not been demonstrated in presbyopic patients. Beta-adrenergic antagonists like timolol have been used topically to control elevated intraocular pressure, but can cause significant systemic side effects.
There are no currently available treatments for presbyopia based on therapeutically manipulating the autonomic innervation of the ciliary muscle. In 1972, Eskridge reported a brief increase in the maximum accomodative response in a 36 year old subject treated with the parasympathomimetic drug eserine (Am. J. Optometry, August, 1972, pp. 632-635). A similar transient gain in accommodation was measured after treating subjects with the alpha-1 antagonist thymoxamine (Zetterstrom, Acta Ophthalmologica 65:699-704, 1987). The use of alpha-2 agonists was not suggested in these references.
No attempt has been made to utilize the accommodation-enhancing effect of parasympathomimetics or of sympatholytic drugs in any way for the treatment of presbyopia. Specifically, these drugs have not been used either to delay the onset of clinically evident presbyopia, or to treat clinically evident presbyopia in conjunction with concurrent use of corrective lenses.
Compounds which decrease adrenergic tone by acting at alpha-adrenergic receptors are currently available for use in the eye and comprise two types, the alpha-1 antagonists and the alpha-2 agonists. Alpha-1 adrenergic antagonists, when used in the eye for blocking pupillary mydriasis, are known to cause vasodilation and marked hyperemia, or reddening, of the eyes, often associated with discomfort.
Compounds that have alpha-2 adrenergic agonistic activity are considered relatively safe drugs for topical use. For example, compounds that have alpha-2 adrenergic agonistic activity are currently marketed for topical use in relief of eye redness, although the alpha-2 activity is not believed to be responsible for the therapeutic effect. In addition, alpha-2 agonists are used for decreasing intraocular pressure.